WO2018080324A1 - Réseau de manipulateurs d'aiguille pour injection de cellules biologiques - Google Patents

Réseau de manipulateurs d'aiguille pour injection de cellules biologiques Download PDF

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Publication number
WO2018080324A1
WO2018080324A1 PCT/NZ2017/050140 NZ2017050140W WO2018080324A1 WO 2018080324 A1 WO2018080324 A1 WO 2018080324A1 NZ 2017050140 W NZ2017050140 W NZ 2017050140W WO 2018080324 A1 WO2018080324 A1 WO 2018080324A1
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WO
WIPO (PCT)
Prior art keywords
manipulator
array
interconnect
stage
needle
Prior art date
Application number
PCT/NZ2017/050140
Other languages
English (en)
Other versions
WO2018080324A9 (fr
Inventor
Arunava Steven BANERJEE
Original Assignee
Mekonos Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2016904437A external-priority patent/AU2016904437A0/en
Priority to US16/346,525 priority Critical patent/US11680277B2/en
Priority to KR1020197015608A priority patent/KR102470238B1/ko
Priority to CN201780081096.0A priority patent/CN110418844B/zh
Priority to CA3041777A priority patent/CA3041777A1/fr
Priority to SG11201903797SA priority patent/SG11201903797SA/en
Application filed by Mekonos Limited filed Critical Mekonos Limited
Priority to KR1020227040477A priority patent/KR102649456B1/ko
Priority to EP17863767.4A priority patent/EP3532622A4/fr
Priority to AU2017349494A priority patent/AU2017349494B2/en
Publication of WO2018080324A1 publication Critical patent/WO2018080324A1/fr
Publication of WO2018080324A9 publication Critical patent/WO2018080324A9/fr
Priority to US18/312,076 priority patent/US20240018549A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/89—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microinjection
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B25—HAND TOOLS; PORTABLE POWER-DRIVEN TOOLS; MANIPULATORS
    • B25J—MANIPULATORS; CHAMBERS PROVIDED WITH MANIPULATION DEVICES
    • B25J7/00—Micromanipulators
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/02—Form or structure of the vessel
    • C12M23/12—Well or multiwell plates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/50—Means for positioning or orientating the apparatus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M3/00—Tissue, human, animal or plant cell, or virus culture apparatus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
    • C12M33/04—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus by injection or suction, e.g. using pipettes, syringes, needles
    • C12M33/06—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus by injection or suction, e.g. using pipettes, syringes, needles for multiple inoculation or multiple collection of samples
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion

Definitions

  • This disclosure relates to improvements in respect of manipulation via needles for injecting biological cells.
  • Injecting biological cells can be achieved by using a microneedle or nanoneedle to penetrate the cell to deliver an agent to be injected.
  • Conventional approaches involve using a device to move the needle in 3-D.
  • Conventional devices use micro- engineered machine (MEMS) technologies involving devices formed from silicon wafer.
  • MEMS micro- engineered machine
  • the manipulator array can further comprise an interconnect, wherein the interconnect comprises connections to the actuator.
  • the manipulator array further comprises a plurality of interconnects, wherein each interconnect comprises connections to the actuator, and wherein each interconnect is associated with a manipulator.
  • the interconnect can comprise a local interconnect, a transitional interconnect and a universal interconnect, wherein the universal interconnect is connected to the transitional interconnect, and the transitional interconnect is connected to the local interconnect.
  • the interconnect is located substantially at a side of the manipulator array.
  • the interconnect is located substantially at a periphery of the manipulator array.
  • a manipulator array comprising a substrate, a plurality of manipulators arranged on the substrate, and a plurality of sub-arrays.
  • Each manipulator can comprise a needle, a stage, a tether, and an actuator, wherein the needle is mounted to the stage, the stage is connected to the actuator by the tether, and the actuator is operable to apply tension in at least one axis to actuate the stage in a direction to manipulate the needle.
  • Each sub-array can comprise a portion of the plurality of manipulators, and interconnects formed on each side of each sub-array, wherein the plurality of sub-arrays are arranged together on the substrate with at least a portion of the interconnects located at a periphery of the manipulator array.
  • each manipulator comprises a plurality of actuators operable to apply tension in more than one axis to actuate the stage in a direction to manipulate the needle.
  • At least one sub-array of the plurality of manipulators is three-sided. At least one sub-array can substantially form a triangle. Alternatively, the sub- arrays are arranged to substantially form a hexagon.
  • the interconnects comprise connections to the actuator, and wherein each interconnect is associated with a manipulator.
  • the interconnects can comprise a local interconnect, a transitional interconnect and a universal interconnect, wherein the universal interconnect is connected to the transitional interconnect, and the transitional interconnect is connected to the local interconnect.
  • the manipulator array is operable to receive applied voltages at the interconnect, the voltages generating electrostatic forces to cause the actuator to apply tension so as to actuate the stage transverse to a plane parallel with the manipulator array to manipulate the needle.
  • the manipulator array is operable to receive applied voltages at the interconnect at a periphery of the device, the voltages generating electrostatic forces to cause the actuator to apply forces so as to actuate the stage parallel to a plane parallel with the manipulator to move the needle with respect to the associated micro-chamber of the cell trap.
  • the manipulator array is operable to receive applied voltages at the interconnect at a periphery of the device, the voltages generating electrostatic forces to cause the actuator to apply forces so as to actuate the stage transverse to a plane parallel with the manipulator to move the needle with respect to the associated micro-chamber of the cell trap.
  • Figure 2 illustrates an actuation stage of a single-unit manipulator, in accordance with various embodiments.
  • Figure 3 illustrates actuators applying forces to an actuation stage from three different directions, in accordance with various embodiments.
  • Figure 6 illustrates a single-unit manipulator with four actuators included in an array of needle manipulators, in accordance with various embodiments.
  • Figures 9a, 9b and 9c illustrate axes of force of a single-unit manipulator, in accordance with various embodiments.
  • Figure 10 depicts an architecture for an array of single-unit manipulators, in accordance with various embodiments.
  • Figure 14 illustrates wires of an interconnect, in accordance with various embodiments.
  • Figure 15 illustrates displacement in various axes of an actuation stage included in a single-unit actuator, in accordance with various embodiments.
  • Figure 16 illustrates displacement in various axes of an actuation stage included in a single-unit actuator, in accordance with various embodiments.
  • Figure 19 is a picture of a biological cell which has been injected, in accordance with various embodiments.
  • Figure 20 schematically illustrates a mechanical system a representing single-unit manipulator for the purpose of stiffness modelling, in accordance with various embodiments.
  • Figures 21a and 21b schematically illustrate a tether under longitudinal stress and experiencing longitudinal strain for the purposes of analysis, in accordance with various embodiments.
  • Figure 23 illustrates a mechanical system representing a single-unit manipulator for the purpose of stiffness modelling, in accordance with various embodiments.
  • Figure 24 illustrates a mechanical system representing a single-unit manipulator for the purpose of stiffness modelling, in accordance with various embodiments.
  • Figure 26 illustrates an array including an arrangement of interconnects, in accordance with various embodiments.
  • Figure 27 illustrates an array including an arrangement of interconnects, in accordance with various embodiments.
  • Figure 28 illustrates a single-unit manipulator with a single actuator included in an array of needle manipulators, in accordance with various embodiments.
  • Figure 29 illustrates an array of needle manipulators, in accordance with various embodiments.
  • Figure 30 illustrates a device including a cell trap and parallel-manipulator, in accordance with various embodiments. It is to be understood that the figures are not necessarily drawn to scale, nor are the objects in the figures necessarily drawn to scale in relationship to one another. The figures are depictions that are intended to bring clarity and understanding to various embodiments of apparatuses, systems, and methods disclosed herein. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. Moreover, it should be appreciated that the drawings are not intended to limit the scope of the present teachings in any way.
  • the terms “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “have”, “having” “include”, “includes”, and “including” and their variants are not intended to be limiting, are inclusive or open-ended and do not exclude additional, unrecited additives, components, integers, elements or method steps.
  • a process, method, system, composition, kit, or apparatus that comprises a list of features is not necessarily limited only to those features but may include other features not expressly listed or inherent to such process, method, system, composition, kit, or apparatus
  • the term 'substantially form a triangle' or similar refers generally to shape which has a base suitable for providing a relatively wide side suitable for providing an electrical interconnect and has a relatively narrow end compared to the wide area, such as an apex in one example, which is suitable for arranging beside similar shapes to pack the shapes more densely than allowed by the relatively wide side providing an interconnect.
  • the term 'substantially form a hexagon' refers generally to a six- sided shape which allows packing of shapes with a relatively wide base suitable for providing an electrical interconnect and with adjacent sides at acute angles to the relatively wide base, such as the triangle in one example.
  • the term 'mounted' refers generally to any means by which a needle is located or connected to an actuation stage, including forming the needle integrally with the actuation stage.
  • a direction' refers generally to a direction of force respect of whether that force is applied using tension in a given direction, compression, stress or other means known to the reader.
  • the phrase 'manipulate', 'manipulator' or the like refers generally to moving a needle such as to locate the needle with respect to a biological cell for penetration of the cell by the needle.
  • Figure 1 illustrates a nanorobot or microrobot in the form of a single-unit needle manipulator 1 which is included in an array of needle manipulators in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the single-unit manipulator 1 has a manipulation stage 2 on which a needle 3 is mounted.
  • Needle 3 can be of a type suited to penetrate an object or cell to deliver, or inject, an agent to the object or cell interior.
  • the injected object or cell may be a biological cell, wherein needle 3 can be of a type suited to penetrate biological cells to deliver, or inject, an agent to the cell interior and/or cell nucleus.
  • the stage 2 can be located above a tower 4 which can be electrically charged relative to the stage 2 to apply electrostatic forces to the stage 2.
  • the stage and tower may be referred to collectively as a parallel-plate actuator, wherein the opposing surfaces on the stage and tower are electrostatically charged when a voltage is applied across them.
  • Electrostatic forces between the tower 4 and stage 2 can actuate the stage 2 in a Z-axis.
  • Z-axis actuation may be the only actuation needed to provide the movement necessary to affect appropriate cell or object penetration by needle 3.
  • This Z-axis can be considered the central axis of the tower 4 as shown in Figure 1.
  • the stage 2 can also be actuated in different axes lying in an X-Y plane, in the plane of the manipulator 1 as shown in Figure 1, by tethers 5a, 5b and 5c.
  • Stage 2 can be configured to manipulate a needle 3 suitable for penetration of objects on this scale of a biological cell.
  • the stage 2 may be referred to as a micro- stage or nano-stage.
  • the tethers 5a, 5b and 5c tether the stage 2 to actuators 6a, 6b and 6c respectively.
  • the actuators 6 can be located so that forces transferred by the tethers 5 can be in three different axes in the X-Y plane. Each tether 5a/5b/5c can apply tensile forces.
  • Actuators 6 can serve to apply forces from three different directions A, B and C.
  • the actuators 6 can be arranged at 120° intervals about stage 2.
  • Tether beams 7a, 7b and 7c of actuators 6a, 6b and 6c can connect each of tethers 5a, 5b and 5c to three support beams 8.
  • the support beams 8 support comb- features, or comb-like electrostatic actuators (not shown).
  • the actuator 6a can have support beams 8a1 , 8a2, and 8a3.
  • Actuators 6a and 6c similarly have support beams 8b1/8b2/8b3 and 8c1/8c2/8c3 respectively.
  • FIG 2 illustrates a portion of the single-unit manipulator, such as that illustrated, for example, in Figure 1, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • Electrostatic comb features (not shown) can be located in the same plane as the support beams 8 shown, for example, in Figure 1.
  • the comb- features may be referred to as comb-drive actuators or comb-drives.
  • the comb- features (not-shown) can be configured to apply force on the support beams 7 in the X-Y axis.
  • the parallel-plate actuator including the central micro-stage 2 and the tower 4 underneath it can be configured to apply force on the tethers 5 in the Z axis.
  • the actuators can have a set of comb-features (not shown) on the support beams 8 and another opposing set of comb-features (not shown) on the manipulator body.
  • the two opposing sets of comb-features can be charged relative to each other to generate an electrostatic force in the X-Y axis, providing a comb- drive.
  • the opposing micro-stage 2 and the tower 4 of the parallel-plate actuator can be charged relative to each other to generate an electrostatic capacitive force in the Z axis.
  • Spring-flexure beams 9a, 9b and 9c connect and anchor support beams 8a, 8b and 8c to the substrate 10 of the manipulator 1.
  • the spring-flexure beams by nature of their stiffness, generate mechanical forces to allow support beams 8 and tethers 7 to move.
  • Spring-flexure beams 9a/9b/9c can be configured and aligned to connect and anchor support beams 8a, 8b and 8c to a substrate 10 of the manipulator 1.
  • the spring-flexure beams 9 allow the support beams 8 and tethers 7 to move under the effect of the actuators 6.
  • Tension applied to the stage 2 by a tether 5 connected to a respective actuator 6 can apply a force to the stage 2 in the direction of the respective actuator 6.
  • Control of the forces applied to the stage 2 in the direction of each actuator 6 individually allows the stage 2 to be actuated so as to manipulate the needle 3.
  • tethers 5 can stretch, and movement of the stage 2 can be dependent on stretching, or strain, of the tethers 5 as well as flexing of the spring-flexure beams 9.
  • the three tethers 5 of the single-unit manipulator connect actuators in three respective directions to a central stage to provide an elastic support structure for the stage 2.
  • three support beams 8, provided for each actuator 6 of the single-unit manipulator 1 provide a support structure to hold the opposing comb-features and can act as a connecting element between spring- flexure beams 9 and tether beams 7, which are connected to tethers 5.
  • Figure 3 illustrates a single-unit manipulator 1 with actuators 6a, 6b and 6c, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the actuator 6b is activated to pull support beams 8a while 6a and 6c are not activated.
  • the effect shown in Figure 3 is to manipulate the needle 3 mounted on the stage 2 in the direction of the actuator 6b. Similar or equivalent effects might also be achieved by each of the actuators 6 being activated with actuator 6b being activated by a greater degree relative to the others.
  • the stage 2 can be actuated by electrostatic charges on the front face of the tower 4, or by the parallel-plate actuator, to manipulate the needle 3 downward into the page (not shown) .
  • FIG. 4 gives a schematic illustration of a comb-drive 11, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the comb-drive 11 can include a movable comb 12, which can be mounted on support beam 8.
  • the comb- drive 11 can also include a fixed comb 13, which can be mounted on the substrate 10 of manipulator 1.
  • the movable comb 12 can include a set of fingers 14. As illustrated, a set of opposing and offset fingers 15 can be provided on the fixed comb 13. Offsetting the fingers 15 from fingers 14 can allow both sets of fingers to be drawn together to overlap in the X-Yaxis.
  • Figure 4 further illustrates a length 16 of the fingers, which can be the same for each set 14 and 15, but may differ in length as desired.
  • Figure 4 also illustrates a spacing 17 between opposite combs 12 and 13 and an overlap 18 of opposite combs 12 and 13.
  • the combs 12 and 13 can form electrodes that can form electric fields to draw the combs 12 and 13 towards each other if the combs 12 and 13, acting as electrodes, are electrostatically charged relative to each other.
  • FIG. 5 illustrates electric fields generated by electrostatic charges applied to fingers 14 relative to fingers 15, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein. Specifically, Figure 5 shows fields 19 attracting overlapping parts of fingers 14 and 15. Also shown in Figure 5 are fields 20 between the ends of fingers 14 or 15 and fields 21 between fingers 14 or 15 and sides of fingers 15 or 14.
  • fields 19 and 21 attract fingers 15, they can cancel each other's effect, leaving, for example, an axial back-and-forth motion of the fingers, thus pulling the support beams 8, tethering beam 7, tethers 5 and stage 2.
  • the electrostatic charges can be applied via support beams 8 and the substrate 10.
  • the fingers 14 form part of the comb 12, which are mounted on the support beam 8, while the fingers 15 form part of the comb 13, mounted on the substrate 10.
  • the electrical fields illustrated correspond to a difference in charge, or opposite charge, applied to the combs 12 and 13.
  • Figure 28 illustrates a nanorobot or microrobot in the form of a single-unit needle manipulator 1b which is included in an array of needle manipulators in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the single-unit manipulator 1b has, as discussed above, a manipulation stage 2 on which a needle 3 is mounted.
  • Needle 3 can be of a type suited to penetrate an object or cell to deliver, or inject, an agent to the object or cell interior.
  • the injected object or cell may be a biological cell, wherein needle 3 can be of a type suited to penetrate biological cells to deliver, or inject, an agent to the cell interior and/or cell nucleus.
  • the stage 2 can be located above a pillar, or tower, 4 which can be electrically charged relative to the stage 2 to apply electrostatic forces to the stage 2.
  • Stage 2 and pillar 4 can form a parallel-plate actuator.
  • Electrostatic forces between the pillar 4 and stage 2 can actuate the stage 2 in a Z-axis causing vertical displacement of the stage 2 relative to the stage 4 and actively deflecting the tether (of cantilever beam) 5.
  • This Z-axis can be considered the central axis of the pillar 4 as shown in Figure 28.
  • the Z-axis actuator is the only actuator shown as it provides the movement necessary to affect appropriate cell or object penetration by needle 3. This single actuation provides advantages as discussed in detail herein.
  • Single axis actuation is particularly useful when an accompanying cell trap (as discussed in detail below) enables close control of the cell or object provided within its micro chambers (as discussed in detail below) such that Z-axis actuation provides all requisite movement necessary for needle penetration of the trapped cell.
  • Figure 29 illustrates a possible architecture for packing and electrically connecting single-unit manipulators 1b onto a wafer using metal interconnects 134, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • FIG. 6 illustrates a needle manipulator 101, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the needle manipulator 101 has a stage 102 on which a needle 103 is mounted. Tethers 105a to 105d tether the stage 102 to four actuators 106a to 106d.
  • the manipulator 101 of Figure 6 has 4 actuators arranged in two orthogonal axes, such as X-axis and Y-axis, for example, as two pairs of opposing actuators 106.
  • the manipulator 101 has an approximately square footprint, and the stage 102 and needle 103 are manipulated by opposing tension forces from each of the pair of actuators 106a and 106c and also by opposing tension forces from the opposing pair of actuators 106b and 106d.
  • the metal pads 107 provide the electrical connections to the manipulator 101.
  • Figure 7 illustrates how single unit manipulators 1 such as that illustrated, for example, in Figure 1 can be packed into an array 150 of manipulators, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the effect of electrical coupling can be considered.
  • a transition of single unit manipulators from four-sided to three-sided actuators not only can reduce the number of electrical interconnects on every side by two, but also can increase the density of microrobots that can be packed into a single parallel architecture.
  • Figure 8 illustrates how single unit manipulators 101 such as that illustrated, for example, in Figure 6 can be packed into an array 155 of manipulators, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • Figures 9a, 9b and 9c illustrate three single-unit manipulators, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • Figure 9a shows a manipulator 301 with tethers 305a and 305b connected to actuators (not shown) arranged so that the tethers 305a and 305b are orthogonal.
  • Figure 9b illustrates a single-unit manipulator 401, similar to single-unit manipulator 1 of Figure 1, with tethers 405a, 405b and 405c.
  • Figure 9c shows a single-unit manipulator 501, similar to single-unit manipulator 101 of Figure 6, with tethers 505a, 505b, 505c and 505d.
  • FIG. 10 illustrates an architecture for packing single-unit manipulators 101 onto a wafer, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • FIG 11 illustrates a manipulator array 130 (or multiple-needle manipulator 130), in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the multiple-needle manipulator 130 can include a parallel array of single-unit manipulators 1 as illustrated, for example, in Figure 1.
  • each single- unit manipulator 1 can have a stage 2 and three actuators 6 can be positioned to provide a force in a different direction to the stage 2.
  • the actuators 6 can be arranged, for example, at 120° intervals about the stage 2.
  • each single-unit manipulator 1 can have a minimum footprint shape dictated by the actuators 6.
  • Figure 11 further shows a number of single-unit actuators 1 arranged, or 'packed', into sub- arrays 131 which form a parallel-array 132 of the multiple-needle manipulator 130.
  • FIG 12 shows six sub-arrays 131a to 131 f .
  • Each sub-array 131 has an interconnect 133 for the single-unit manipulators 1.
  • the interconnect 133 allows connection of a voltage source to provide an electrostatic field within each comb- drive 11 to activate each actuator 6 (see, for example, Figures 1-4).
  • the interconnect 133 can allow for individual actuation of each actuator 6 of each single-unit manipulator 1.
  • the interconnect 133 shown in Figure 11 has three rows 134 (also referred to as local interconnect), 135 (also referred to as transitional interconnect) and 136 (also referred to as universal interconnect) of connections.
  • interconnects are metallic wires commonly fabricated out of Copper (Cu) or Aluminium (Au) that forms the three rows connecting the different parts of the single-unit manipulators to the external circuit.
  • the support beams 8 holding the fixed comb-fingers on each of three sides A, B and C (refer back to Figure 1) have their individual interconnects each at a single applied potential while the support beams 8 holding the free comb-fingers on each of the three sides A, B and C have a single interconnect at a single potential that also charges the stage 2.
  • the tower 4 has a separate interconnect at a different potential.
  • every single-unit manipulator can have, for example, five interconnections, leading to an array of such actuators all resulting in different rows 134, 135 and 136 of interconnections in order to avoid wire collision when connecting to an external circuit.
  • the interconnect 133 is provided via universal interconnect 136 of each sub-array 131.
  • the arrangement of multiple-needle manipulator 130 can be determined by analysis of the layout such as interconnect routing, floor planning of the placement of single-unit manipulators 1.
  • the arrangement can include considerations distinct from the case of high-performance IC circuit technologies such as from IntelTM and AMDTM. In these technologies, factors such as interconnect parasitic impedances, power dissipation, noise, bandwidth, transistor gate delays and loads are critical with an interconnect density of 1-4 million per square centimetres.
  • the density of the interconnections of the interconnect 133 can be orders of magnitude lower than for IC technologies due to the significant size of the single-unit manipulators 1 ranging in a few millimetres such as, for example, 1-6mm, as compared to transistors of less than 100nm in size.
  • interconnection capacitance includes the capacitance between the interconnect 133 and the substrate; and the coupling capacitance between neighbouring interconnection rows 134, 135 and 136 or any other neighbouring interconnection rows or wires that may be used.
  • FIG. 12 illustrates an interconnect 133 that can be located, for example, at an edge or periphery of each triangular array 131 a to 131 f.
  • Each triangular array 131, or functional block can include an arrangement of single-unit manipulators 1.
  • Each single-unit actuator can be connected via local interconnects 134 that can include lines which extend to transitional interconnects 135 that run through a two-sided periphery 139 of the triangle arrays. These transitional interconnects can be wider and taller than local interconnects 134 provided for each single-unit manipulator 1 in order to provide lower resistance.
  • the transitional interconnects 135 extend to the universal interconnects 136 that provide connections between every functional block and deliver applied voltage from an external power supply to the chip.
  • the transitional interconnects can be the longest in length in the layout of the parallel architecture and are of generally lower resistivity.
  • metallisation for the various interconnects can include of low stress (40-140 MPa) titanium-tungsten (TiW) forming the main adhesion layer and Au as the main conductor.
  • Au can be sputtered or plated to different thickness values to enhance skin depth and conductivity.
  • Cu can be used in place of Au with the advantage of the lower cost.
  • Cu may also have the advantage of being widely used as a standard material for primary interconnection due to its low resistivity.
  • the resistance of a conductor with a rectangular cross-section is given by,
  • p is the material resistivity
  • I, W, and H are the length, width, and thickness of the interconnect, respectively.
  • the bulk resistivities of Au and Cu are 2.2 ⁇ -cm and 1.71 ⁇ -cm, respectively.
  • the resistivity can increase due to surface and grain boundary scattering. This is because the electrons experience more collisions at the surface, increasing the effective resistivity.
  • ⁇ of copper is 42.1nm at 0°C.
  • k d/ ⁇ is the ratio of the thin film thickness to the electron mean-free path
  • p is the fraction of the electrons that are elastically scattered at the surface.
  • Grain boundaries known to the reader act as partially reflecting planes, with grain sizes scaled linearly with wire dimensions.
  • the electrons face relatively more grain boundary scattering, thereby further increasing the effective resistivity as is given by this equation,
  • d g s the grain diameter
  • p g is the grain boundary reflection coefficient with a value ranging between 0 and 1.
  • the resistivity increases linearly with temperature, as given by,
  • ⁇ is the temperature coefficient of resistivity and ⁇ is the temperature difference with respect to a reference temperature. Since ⁇ decreases with increasing temperature, the k value in Equation (2) becomes larger, thereby leading to a smaller value of. Therefore, ⁇ value of a thin wired interconnect is smaller than that of a bulk metal.
  • Conventional interconnects such as used in IC chips, can generally be designed based on fast transmission of signals between the transistors, and generally use design tree models such as A-tree, P-tree, H-tree, X-tree and C-tree to minimize the wire length of the interconnects.
  • design tree models such as A-tree, P-tree, H-tree, X-tree and C-tree to minimize the wire length of the interconnects.
  • design tree models such as A-tree, P-tree, H-tree, X-tree and C-tree to minimize the wire length of the interconnects.
  • design tree models such as A-tree, P-tree, H-tree, X-tree and C-tree
  • the relatively simpler layout of the parallel-manipulator 130 includes non-orthogonal wiring connections. This wiring connection orientation is due, at least in part, to the relative arrangement of the manipulators 1 and their actuators 6.
  • the architecture of parallel-manipulator 130 can include a plurality of single-unit manipulators 1, each with a plurality of actuators 6 (for example, three) arranged into triangle arrays 131, which can be arranged in a hexagon with interconnects 133 at the periphery of the hexagon.
  • This architecture minimizes the distance of lines from interconnects 133 to actuators 6 yet maximises the density of single-unit manipulators 1 in a given surface area available on a chip.
  • the architecture illustrated in Figure 12 which may be described as having triangular-island structures in the physical layout of the array, takes advantage of splitting the interconnect into smaller segments such as local 134, transitional 135 and universal 136 to reduce any signal delay occurring in the various interconnects.
  • FIG. 12 illustrates a universal interconnect 136 in the array 130.
  • the universal interconnect receives control voltages to activate the actuators 6 and the parallel plate actuator formed between stages 2 and towers 4. The voltages control the manipulators 1.
  • Figures 26 and 27 illustrate interconnections between the universal interconnects of Figure 12 and the single-unit manipulators 1, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • transitional interconnects 135 located at a side periphery of the triangle formed by an array 131 connect to universal interconnects 136.
  • the transitional interconnects 135 form step-wise wedge-shaped regions in the sub-array 131.
  • Local interconnects 134 connect between transitional interconnects 135 and single-unit manipulators 1.
  • the local interconnects form step-wise wedge-shaped regions in the sub-array 131.
  • Figure 30 illustrates a device 170, which can be a cell injection device, which can include a cell trap 160 used in conjunction with the parallel-manipulator 130 to trap cells and locate individual cells in spatial communication with a respective single- unit manipulator 1.
  • the single-unit manipulators could then be used, for example, for injection by needles 3 manipulated by stages 2, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the cell trap 160 can be formed from a substrate made from, for example, a glass, a semiconducting material, a metal, a polymer, a composite, a nanostructured material, a crystalline material, or a combination thereof.
  • Figure 13 illustrates the cell trap 160 configured to capture a plurality of cells, for example, by holding individual cells 161 in respective micro- chambers 162.
  • the micro-chambers 162 can be arranged with a separation or pitch to match the separation or pitch of the single-unit manipulators 1 in the multiple-manipulator array 130, such that each micro-chamber 162 can be in spatial communication with a respective single-unit manipulator 1.
  • the cells 161 can be added to the cell trap 160 by an input port 163.
  • cell trap 160 can be formed on numerous types of substrate materials including, for example, a glass substrate 165.
  • Figure 14 illustrates three rows 141, 142 and 143 of interconnects that are provided for interconnect wires 144.
  • Figure 15 illustrates displacement of a stage 2 of the single-unit manipulator 1, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the displacement is shown as displacement caused by given tethers 5. Both simulated (solid line) and analytical (dotted line) displacements are depicted.
  • Figure 16 illustrates displacement of the stage 2 depicted as X-Y displacement or device in-plane displacement and as Z-displacement, or distance from the tower 4 and to the stage 2, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • Displacements of the stage 2, such as depicted in Figures 15 and 16 can correspond to manipulation via the needle using applied voltages, or electrostatic charges, applied to metal pads (not shown) on actuators 6 to generate forces transferred to the stage 2 via tethers 5 and by voltages, or electrostatic charges, applied to metal pads (not shown) on the towers 4.
  • These voltages, or electrostatic charges will be the result of voltages applied at interconnects 133 and the effects discussed can occur in parts of the multiple-manipulator 130 such as in the transitional interconnects 135 and local interconnects 134.
  • an in-plane X-Y displacement of more than, for example, 36 ⁇ m can be achieved at 160 V in one direction in a pull-mode.
  • it can achieve a total in-plane displacement of more than 72 ⁇ m ( ⁇ 36 ⁇ m) at 160 V in a pull-pull mode.
  • tether 5 length nor the thickness of the suspended actuator structure affects the in-plane motion significantly. This is also true if instead of actuating one side, two sides are simultaneously actuated for better targeted control of the microneedle 3.
  • the stretching in the tethers is also negligible in the order of sub nanometres.
  • the out-of-plane Z displacement can increase as the length of the tethering beams increase or the thickness of the suspended structure decreases as shown, for example, in Figure 16.
  • an out-of-plane displacement of more than 6 ⁇ m can be achieved at 30 V with a tethering beam length of 800 ⁇ m. Since the out-of-plane stiffness of the actuator reduces significantly by such change in dimensions, the same displacement can be achieved at 22 V with a tethering beam length of 1000 ⁇ m and at 17 V with a tethering beam length of 1200 ⁇ m.
  • square manipulator 101 with actuation by a pair of actuators on either side is slightly greater than that with a triangular manipulator 1.
  • square manipulator can achieve an in-plane (X-Y) motion of around 38 ⁇ m with actuation by two actuators compared to slightly above 36 ⁇ m with the triangular manipulator Adding an extra actuator does add to the total stiffness of the structure.
  • square manipulator achieves a motion of around 4.5 ⁇ m compared to more than 6 ⁇ m with a triangular manipulator. It becomes evident that a 40% increase in single-unit manipulators, as well as a performance enhancement, can be achieved by reducing an extra side.
  • Bond metal pads (not shown) used in single-unit manipulators 1 and multiple- needle manipulator 130 provide electrodes for electrostatic charge applied separately to the fixed comb-fingers 15, moving comb-fingers 14 which provide in- plane (X-Y) actuation and the stage 2 and tower 4 which provides vertical micro- stage manipulation for the stage 2 and needle 3.
  • the pads can be formed of a thin layer of Titanium-Tungsten and gold (-850 A) with low film stress. They can be fabricated, for example, by blanket physical deposition of the metal film followed by wet chemical etching and patterning. The pads can sit on a silicon oxide insulating layer (not shown).
  • the metal pads (not shown) can be wire bonded to the printed circuit board and external electronics at the interconnect 133.
  • the multiple-needle manipulator 130 can be formed of a silicon-on-insulator wafer (not shown). This is a sandwich structure including a device layer (active layer) on top, a buried oxide layer (insulating Si02 layer) in the middle (e.g., a few microns in thickness), and a handle wafer (bulk silicon) in the bottom. Such isolation of the device layer from the bulk silicon layer results in lower parasitic capacitance can significantly improve the performance and reduce the power consumption of integrated circuits.
  • the bottom substrate can be a standard silicon wafer several hundred times the thickness of the buried oxide layer.
  • the tower 4 can be a tower shaped electrode (made of, for example, silicon) located under the central stage 2.
  • Tower 4 provides an electrostatic, or capacitive, force for the stage 2, thereby resulting in deflections of the tethers and spring flexure beams 9.
  • the tower top surface area (not indicated) can be greater than the surface area of the stage 2 by a factor of, for example, two to three in order to have significant surface area still available to produce attractive electrostatic force after in-plane (X-Y) motion caused by the actuators 6 makes the location of the needle 3 ready for out-of-plane (Z) motion.
  • the cross-section (not indicated) of the tower 4 can be circular due to the circular geometry of the micro-stage, with enough access area on each side for larger displacements, in comparison to other geometries.
  • the movement described here in reference to X, Y and Z axes may be referred to as manipulation as it is used to manipulate the needle 3 for injecting a cell for example.
  • the needle 3 may be referred to as a microneedle or nanoneedle.
  • the needle 3 can be assembled onto the micro-stage or stage 2, which is circular in shape, in order to provide geometric symmetry for the particular three-sided manipulator 1. Since an attractive capacitive force between the stage 2 and the bottom tower (e.g., silicon tower) or tower 4 is proportional to the surface area, a larger area of the top or cross-section of the tower 4 will result in larger capacitance. Thereby, a larger vertical force for penetration through the cell membrane will be generated in the Z- axis. Nonetheless, there can be a proportional relationship between increasing the surface area of the micro-stage and achieving an optimum surface area of the actuator, critical for the parallel architecture.
  • the bottom tower e.g., silicon tower
  • Figure 17 illustrates a single-unit manipulator as a system 200 comprising a stage 202 which is acted upon in the Z-axis by electrostatic attraction with a tower 204 and a restoring bias 205 or spring with spring constant k, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • the bias 205 in this system is the combined effect of tethers 5, which experience strain, and spring flexure beams 9.
  • forces on the stage may also be biased, actuated or both in part by actuators 6.
  • Actuation of the stage 2 can involve balancing forces applied by the actuators 6 and tower 4, which can be controlled by voltages applied at interconnects 133 and forces applied by spring flexure beams 9 and tethers 5.
  • the displacement achieved with one actuator functioning in a single-unit manipulator with four actuators can be less than that achieved with a single-unit manipulator with three actuators.
  • a single-unit manipulator with four actuators can achieve an in-plane motion of around 27 ⁇ m with a single actuator functioning in comparison to slightly above 36 ⁇ m with a single-unit manipulator with three actuators. Nonetheless, the displacement achieved with a single-unit manipulator with four actuators with two actuators functioning is slightly greater than that with a single-unit manipulator with three actuators design.
  • a single-unit manipulator with four actuators can achieve an in-plane motion of around 38 ⁇ with two actuators functioning compared to slightly above 36 ⁇ m with the single-unit manipulator with three actuators. Adding an extra side (or actuator) does add to the total stiffness of the structure.
  • a single-unit manipulator with four actuators achieves a motion of around 4.5 ⁇ m compared to more than 6 ⁇ m with a single-unit manipulator with three actuators.
  • FIG. 18 shows a 3D volume plot in Figure 18 with respect to a human cell type in Figure 19.
  • This actuator has a tethering beam length of 800 prn, a suspended structure thickness of 10 ⁇ m and an actuator gap of 15 ⁇ m. Given the cell size is about 25 ⁇ m in diameter, the actuator can easily move the nanoneedle over the size of the cell both in-plane and to a reasonable extent in out-of-plane.
  • Figure 20 illustrates for reference a tether 5 as a simple mechanical system for the purpose of analysis, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • Figure 21a and 21b illustrate, for reference below, bending tether 5 and corresponding flexure of spring flexure beams 9, in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • tethers 5a and 5b experience bending in that results in the bending of the spring flexure beams.
  • the parallel plate actuator experiences an electrostatic force in the vertical direction
  • the central stage 2 actuates downwards or upwards and therefore the tethers 5a, 5b and 5c experiences corresponding bending in the Z axis.
  • a single-unit manipulator with three actuators of suspended structure thickness of 10 ⁇ m, an increasing parallel-plate actuator gap, and all the other dimensions are kept constant.
  • the maximum bending and stretching of the tethers 5 and spring flexure beams 9 due to translational and axial deflections can be critical for actuator performance.
  • the motion performance of these beams can be dependent on the effects discussed below.
  • a first effect is minimum longitudinal stretching of tether 5, shown schematically in the mechanical system of Figure 20.
  • a second effect is maximum bending of tethers for 3D (X, Y and Z) motion range with decoupled motion across the axes.
  • Motion coupling is a parasitic behaviour that significantly affects the motion performance and structural integrity of the actuator.
  • a third effect is the relationship between bending of spring flexure beams 9 and bending of tethers 5, as shown in Figure 16.
  • Two of the many important attributes that govern the behaviour of the actuator are bending and longitudinal stretching.
  • Knowledge of stretching of the tethers 5 assists in understanding the fatigue performance under repeated loading of the beams. Stretching can lead to increasing stiffness of the tethers which can affect the overall strength of the structure formed of the stage 2 and tethers 5.
  • the fatigue life of the beams under cyclic loading can be significantly affected with stretching in the tethers 5.
  • plastic behaviour can be induced in these suspended beam structures. This can result in a permanent elongation of the tethers and thus affecting the accuracy of motion performance.
  • the stretching and bending phenomena can be investigated for many different parameters including, for example, the following parameters, due to their significant contribution toward the motion of the actuator: cross-section area (wx h), aspect ratio (w/h) and length (/) of the tether 5 or beam 9.
  • cross-section area (wx h) cross-section area (wx h)
  • aspect ratio (w/h) aspect ratio
  • Three thicknesses 10 ⁇ m, 20 ⁇ m and 25 ⁇ m were used to study the beam behaviours as limiting parameters.
  • the interference in deflection of the tethers 5 and spring flexure beams 9 for both in-plane and out-of- plane actuation were taken into account. Based on these criteria and parameters, six such scenarios were mapped out and analysed to conceptualise suitable beam dimensions.
  • the cross-section area of the beams should not be greater than, for example, 50 ⁇ m 2 , and the aspect ratio not greater than, for example, 0.5, for optimal trade-off between bending and integration of multiple actuators in a parallel architecture. Longitudinal stretching is found to be negligible, several orders of magnitude lower than the 3D bending of the beams.
  • Such design conceptualization and analysis provides critical information in terms of cross-section area and aspect ration of the beams for optimal trade-off between bending and integration of multiple actuators in a parallel architecture.
  • a further effect is in-plane bending of tethers 5 compared with their out-of-plane bending.
  • Figures 22a to 22c illustrate three types of spring flexure beam 9 which may be used in accordance with various embodiments, the features of which can be used as illustrated or in combination with other embodiments disclosed herein.
  • Figure 22a illustrates the type which may be referred to as clamped-clamped.
  • Figure 22b illustrates a type which may be referred to as crab leg.
  • Figure 22c illustrates a type of spring flexure beam 9 which may be described as single folded.
  • the following provides further analysis of the bending and flexing of the tethers 5 and the above-described three types of spring flexure beams 9.
  • the longitudinal stretching of the tether 5 is computed by,
  • the bending of the tether 5 is computed by, where / is the second moment of inertia of the tether 5.
  • the bending of the spring flexure beam 9 is computed by,
  • the out-of-plane stiffness K is, where moment of inertia of shin about x-axis.
  • the axial stiffness is,
  • the out-of-plane stiffness is,
  • the moving electrode pairs will be unstable without the mechanical restoring force in the y-direction.
  • Equation (18) the equivalent negative spring constant as a function of in-plane (X-Y) spring stiffness is,
  • Equation (7) is critical for maintaining the stability of the actuator during in-plane motion. Since the springs on each sides are connected in parallel, the effective in- plane axial spring constant in the direction of motion as derived from the known beam deflection theory is,
  • This in-plane (X-Y) displacement of the stage 2 caused by the pull-pull mode of the comb-drive actuators 6 represents the maximum motion achievable at particular voltages.
  • a matrix model for in-plane grid stiffness of the single-unit manipulator 1 will now be discussed.
  • subscripts indicate the corresponding element number. / is the second moment of inertia of the beam .
  • Equation (31 ) When added and assembled generates the appropriate 14x 14 stiffness matrix on the left hand side. Therefore the two sides are equivalent to each other and not equal due to the different orders of matrix of both sides before assembly. Therefore writing the total structure stiffness equation accounting for the applied electrostatic force on nodes 7 and 5 and force and displacement boundary constraints at the other nodes,
  • the model includes angular components in a mathematical treatment.
  • a transformation matrix can be used to transform the local displacement components into global ones and this result in the global stiffness matrix.
  • In-plane slope-deflection model of the single-unit manipulator will now be described.
  • the in-plane motion of the single-unit manipulator 1 is also analytically modelled using slope-deflection equations, shown in Figure 24, as an additional tool to investigate the design of the actuator.
  • all the joints are considered rigid and the angle between the beams at the joints is constant under the loading. The distortion due to axial and shear stresses are considered negligible.
  • Each side A, B and C consists of an arrangement of comb-drives 11 and spring flexure beams 9 which are connected to stage 2 represented in Figure 24 as 24-D.
  • the tethering beam length is l t and the angle between the corresponding tethering beams is 120°.
  • the final connectivity matrix becomes,
  • tethers 5 may be beams or may be treated analytically as beams.
  • the middle layer of the silicon-on-wafer, of which the multiple-needle manipulator 130 is formed is in the range of a few tenths of a micron to a few microns thick.
  • Embodiment 1 A device comprising a cell trap comprising a plurality of micro- chambers, each micro-chamber configured to hold a cell; and a manipulator array comprising a plurality of manipulators, each manipulator in spatial communication with a respective micro-chamber, wherein each manipulator comprises a needle, a stage, and an actuator, wherein the needle is mounted to the stage, and the actuator is operable to apply force to the stage in a direction to move the needle to penetrate a cell in the respective micro-chamber.
  • Embodiment 2 The device of Embodiment 1 , wherein each manipulator comprises a plurality of actuators operable to apply a plurality of forces to the stage in a plurality of directions to move the needle.
  • Embodiment 3 The device of any of the preceding Embodiments, wherein the manipulator array comprises a plurality of sub-arrays, each sub-array comprising a portion of the plurality of manipulators.
  • Embodiment 4 The device of Embodiment 3, wherein at least one sub-array of the plurality of manipulators is three-sided.
  • Embodiment 5 The device of any one of Embodiments 3 and 4, wherein at least one sub-array substantially forms a triangle.
  • Embodiment 6 The device of any of the preceding Embodiments, the manipulator array further comprising an interconnect, wherein the interconnect comprises connections to the actuator.
  • Embodiment 7 The device of any of the preceding Embodiments, the manipulator array further comprising a plurality of interconnects, wherein each interconnect comprises connections to the actuator, and wherein each interconnect is associated with a manipulator.
  • Embodiment 8 The device of any of Embodiments 6 and 7, the interconnect comprising a local interconnect, a transitional interconnect and a universal interconnect, wherein the universal interconnect is connected to the transitional interconnect, and the transitional interconnect is connected to the local
  • Embodiment 9 The device of any of Embodiments 6 to 8, wherein the interconnect is located substantially at a side of the manipulator array.
  • Embodiment 10 The device of any of Embodiments 3 to 8, wherein the sub-arrays are arranged to substantially form a hexagon.
  • Embodiment 11 The device of any of Embodiments 6 to 10, wherein the
  • interconnect is located substantially at a periphery of the manipulator array.
  • Embodiment 12 A manipulator array comprising a substrate; a plurality of manipulators arranged on the substrate, each manipulator comprising a needle, a stage, a tether, and an actuator, wherein the needle is mounted to the stage, the stage is connected to the actuator by the tether, and the actuator is operable to apply tension in at least one axis to actuate the stage in a direction to manipulate the needle; and a plurality of sub-arrays, each sub-array comprising a portion of the plurality of manipulators, and interconnects formed on each side of each sub- array, wherein the plurality of sub-arrays are arranged together on the substrate with at least a portion of the interconnects located at a periphery of the manipulator array.
  • Embodiment 13 The array of Embodiment 12, wherein each manipulator comprises a plurality of actuators operable to apply tension in more than one axis to actuate the stage in a direction to manipulate the needle.
  • Embodiment 14 The array of any of Embodiments 12 and 13, wherein at least one sub-array of the plurality of manipulators is three-sided.
  • Embodiment 15 The array of any of Embodiments 12 to 14, wherein at least one sub-array substantially forms a triangle.
  • Embodiment 16 The array of any of Embodiments 12 to 15, wherein the
  • interconnects comprise connections to the actuator, and wherein each interconnect is associated with a manipulator.
  • Embodiment 17 The array of any of Embodiments 12 to 16, the interconnects comprising a local interconnect, a transitional interconnect and a universal interconnect, wherein the universal interconnect is connected to the transitional interconnect, and the transitional interconnect is connected to the local
  • Embodiment 18 The array of any of Embodiments 12 to 17, wherein the sub- arrays are arranged to substantially form a hexagon.
  • Embodiment 19 The array of any of Embodiments 13 to 18, wherein the plurality of actuators are operable to apply tension in three directions.
  • Embodiment 20 The array of any of Embodiments 13 to 19, wherein the plurality of actuators is operable to provide tensile forces.
  • Embodiment 21 The array of any of Embodiments 12 to 20, wherein the
  • manipulator array is operable to receive applied voltages at the interconnect, the voltages generating electrostatic forces to cause the actuator to apply tension so as to actuate the stage parallel to a plane parallel with the manipulator array to manipulate the needle.
  • Embodiment 22 The device of any of Embodiments 12 to 21 , wherein the manipulator array is operable to receive applied voltages at the interconnect, the voltages generating electrostatic forces to cause the actuator to apply tension so as to actuate the stage transverse to a plane parallel with the manipulator array to manipulate the needle.
  • Embodiment 23 The device of any of Embodiments 12 to 22, wherein the manipulator array is operable to receive applied voltages at the interconnect at a periphery of the device, the voltages generating electrostatic forces to cause the actuator to apply forces so as to actuate the stage parallel to a plane parallel with the manipulator to move the needle with respect to the associated micro-chamber of the cell trap.
  • Embodiment 24 The device of any of Embodiments 12 to 23, wherein the manipulator array is operable to receive applied voltages at the interconnect at a periphery of the device, the voltages generating electrostatic forces to cause the actuator to apply forces so as to actuate the stage transverse to a plane parallel with the manipulator to move the needle with respect to the associated micro- chamber of the cell trap.

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Abstract

L'invention concerne un dispositif, comprenant un piège à cellules comprenant une pluralité de micro-chambres, chaque micro-chambre étant conçue pour contenir une cellule. Le dispositif peut en outre comprendre un réseau de manipulateurs comprenant une pluralité de manipulateurs, chaque manipulateur étant en communication spatiale avec une micro-chambre respective, chaque manipulateur comprenant une aiguille, un palier et un actionneur, l'aiguille étant montée sur le palier, et l'actionneur étant utilisable pour appliquer une force au palier dans une direction déplaçant l'aiguille pour pénétrer dans une cellule dans la micro-chambre respective.
PCT/NZ2017/050140 2016-10-31 2017-10-31 Réseau de manipulateurs d'aiguille pour injection de cellules biologiques WO2018080324A1 (fr)

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AU2017349494A AU2017349494B2 (en) 2016-10-31 2017-10-31 An array of needle manipulators for biological cell injection
KR1020197015608A KR102470238B1 (ko) 2016-10-31 2017-10-31 생체 세포 주입을 위한 니들 매니퓰레이터들의 어레이(an array of needle manipulators for biological cell injection)
CN201780081096.0A CN110418844B (zh) 2016-10-31 2017-10-31 用于生物细胞注射的针操纵器的阵列
CA3041777A CA3041777A1 (fr) 2016-10-31 2017-10-31 Reseau de manipulateurs d'aiguille pour injection de cellules biologiques
SG11201903797SA SG11201903797SA (en) 2016-10-31 2017-10-31 An array of needle manipulators for biological cell injection
US16/346,525 US11680277B2 (en) 2016-10-31 2017-10-31 Array of needle manipulators for biological cell injection
KR1020227040477A KR102649456B1 (ko) 2016-10-31 2017-10-31 생체 세포 주입을 위한 니들 매니퓰레이터들의 어레이
EP17863767.4A EP3532622A4 (fr) 2016-10-31 2017-10-31 Réseau de manipulateurs d'aiguille pour injection de cellules biologiques
US18/312,076 US20240018549A1 (en) 2016-10-31 2023-05-04 Array of needle manipulators for biological cell injection

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Publication number Priority date Publication date Assignee Title
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CN110418844B (zh) 2024-04-09
SG11201903797SA (en) 2019-05-30
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US11680277B2 (en) 2023-06-20
US20240018549A1 (en) 2024-01-18
US20190300907A1 (en) 2019-10-03
EP3532622A1 (fr) 2019-09-04
KR102649456B1 (ko) 2024-03-19
CN110418844A (zh) 2019-11-05
EP3532622A4 (fr) 2020-06-03
WO2018080324A9 (fr) 2019-04-18
AU2017349494B2 (en) 2024-02-01
CA3041777A1 (fr) 2018-05-03
AU2017349494A1 (en) 2019-06-06
KR20220162811A (ko) 2022-12-08

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